Claims for Patent: 5,756,451

Summary for Patent: 5,756,451

Title:	Platelet aggregation inhibitors
Abstract:	This invention relates to a group of peptides which are, or are related to, platelet aggregation inhibitors isolated and purified from various snake venoms. The instant platelet aggregation inhibitors inhibit (a) binding of Fg or vWF to GPIIb-IIIa more than (b) binding of vitronectin to vitronectin receptor or fibronectin to fibronectin receptor. The peptides are useful as therapeutic agents for the treatment of, and prevention of, platelet-associated ischemic disorders.
Inventor(s):	Robert M. Scarborough, David Lawrence Wolf, Israel F. Charo
Assignee:	COR Therapeutics Inc , Millennium Pharmaceuticals Inc
Application Number:	US08/472,808
Patent Claims:	1. A platelet aggregation inhibitor that inhibits (a) binding of Fg or vWP to GP IIb-IIIa more than (b) binding of vitronectin to vitronectin receptor or fibronectin to fibronectin receptor, which platelet aggregation inhibitor has the formula ##STR7## (1) where K* is a lysyl residue of the formula R.sup.1.sub.2 N(CH.sub.2).sub.4 CHNHCO-- wherein each R1 is independently hydrogen, alky(1-6C) or one R1 is R2 --C═N3, in which: R2 is hydrogen, alkyl(1-6C), a substituted or unsubstituted phenyl or benzyl residue, or NR4 2 in which each R4 is independently hydrogen or alkyl(1-6C), and R3 is hydrogen, allyl(1-6C), phenyl or benzyl, or R2 --C═NR3 is a radical selected from the group consisting of ##STR8## wherein m is an integer of 2-3, and each R5 is independently H or alkyl(1-6C) and one or two --CH2 -- may be replaced by O or S provided said O or S is not adjacent to another heteroatom; (2) where AA1 and AA4 are each independently selected from the group consisting of Gly, Ala, and Ser; n1 is an integer of 0-3; and n4 is an integer of 0-3; (3) where AA2 is selected from the group consisting of tryptophan, phenylalanine, leucine, tyrosine, and valine and n2 is an integer of 0-3; (4) where AA3 is a proline residue or a modified proline residue of the formula ##STR9## wherein one or two of the methylenes of said proline or modified proline residue is optionally replaced by --NR--, --S--, or --O-- wherein R is hydrogen or allyl (1-6C) and n3 is an integer of 0-1; (5) where each of X1 and X2 is independently a residue selected from the group consisting of cysteine, mercaptopropionyl, mercaptovaleryl, and penicillaine, and ##STR10## represents a bond between X1 and X2 ; and (6) where each of Y1 and Y2 is independently a non-interfering substituent or is absent; and (7) where one or more peptide linkages may optionally be replaced by a linkage selected from the group consisting of --CH2 NH--, --CH2 S--, --CH2 CH2 --, --CH═CH-- (cis or trans), --COCH2 --, --CH(OH)CH2 -- and --CH2 SO--; and (8) where all chiral amino acid residues in said formula are of the L configuration; (9) with the proviso that if n3 is 0; either:1) the sum of n2 and n4 must be at least 2; or 2) K* cannot be Har or Lys; or 3) X2 cannot be cysteine, penicillamine, or 2-amino-3,3-cyclopentanemethylene-3-mercaptopropionic acid; or 4) one or more peptide linkages is replaced by said alternate linkage,or a physiologically acceptable salt thereof. 2. The composition of claim 1 wherein Y2 is --NH2, --alanine--NH2, or is absent. 3. The composition of claim 1 wherein Y1 is hydrogen, acetyl, glycine, or is absent. 4. The composition of claim 1 wherein X1 and X2 are selected from the group consisting of cystein, mercrcaptopropionyl, and penicillamine. 5. The composition of claim 1 wherein AA1 is glycine and n1 is 0 or 1. 6. The composition of claim 1 wherein AA2 is tryptophan or phenylalanine. 7. The composition of claim 6 wherein AA2 is tryptophan. 8. The composition of claim 1 wherein K* is lysine, homoarginine, acetimidyl lysine, or phenylimidyl-lysine. 9. The composition of claim 1, wherein:Y3 is --NH2, --alanyl--NH2, or is absent; Y1 is hydrogen, acetyl, glycyl, or is absent; X1 and X2 are selected from the group consisting of peptide-forming residues of cysteine, mercaptopropionyl, and penicillamine; AA1 is glycine and n1 is 0 or 1; AA2 is tryptophan, phenylalanine, leucine, tyrosine, or valine; AA3 is proline, pipecolic acid, or thiazolidine and n3 is 1; and K* is lysine, homoarginine, acetimidyl-lysine, or phenylimidyl-lysine. 10. The composition of claim 9, wherein n1 is 0, n2 is 1, and n4 is 0. 11. The composition of claim 10, wherein:Y2 is NH2 ; Y1 is hydrogen, acetyl, glycine, or is absent; n1 is 0; K* is lysine, homoarginine, acetimidyl-lysine, or phenylimidyl-lysine; X1 and X2 are selected from the group consisting of cysteine, mercaptopropionyl, penicillamine; AA2 is selected from the group consisting of typtophan, phenylalanine, leucine, tyrosine, and valine and n2 is 1; AA3 is proline, pipecolic acid, or thiazolidine and n3 is 1; and n4 is 0. 12. The composition of claim 11, wherein (Gly or Sar) is glycine. 13. The composition of claim 4 in which said platelet aggregation inhibitor is selected from the group consisting ofGly-Cys-Gly-Lys-Gly-Asp-Trp-Pro-Cys-Ala-NH2 ; Gly-Cys-Lys-Gly-Asp-Trp-Pro-Cys-Ala-NH2 ; Cys-Gly-Lys-Gly-Asp-Trp-Pro-Cys-NH2 ; Cys-Lys-Gly-Asp-Trp-Pro-Cys-NH2 ; Cys-Lys-Gly-Asp-Tyr-Pro-Cys-NH2 ; Cys-Lys-Gly-Asp-Phe-Pro-Cys-NH2 ; Cys-Lys-Gly-Asp-Leu-Pro-Cys-NH2 ; Cys-Lys-Gly-Asp-Val-Pro-Cys-NH2 ; Mpr-Lys-Gly-Asp-Trp-Pro-Cys-NH2 ; Mpr-Lys-Gly-Asp-Tyr-Pro-Cys-NH2 ; Mpr-Lys-Gly-Asp-Phe-Pro-Cys-NH2 ; Mpr-Lys-Gly-Asp-Leu-Pro-Cys-NH2 ; Mpr-Lys-Gly-Asp-Val-Pro-Cys-NH2 ; Cys-Lys-Gly-Asp-Trp-Gly-Cys-NH2 ; Cys-Lys-Sar-Asp-Trp-Pro-Cys-NH2 ; Acetyl-Cys-Lys-Gly-Asp-Trp-Pro-Cys-NH2 ; Mvl-Lys-Gly-Asp-Trp-Pro-Cys-NH2 ; Mpr-Lys-Gly-Asp-Trp-Pro-Pen-NH2 ; Mpr-Lys-Gly-Asp-Trp-Thz-Cys NH2 ; Mvl-Lys-Gly-Asp-Trp-Pro-Pen-NH2 ; Mpr-Lys-Gly-Asp-Trp-Pip-Pen-NH2 ; Mpr-Har Gly-Asp-Trp-Pro-Cys-NH2 ; Mpr-Har-Gly-Asp-Trp-Pro-Pen-NH2 ; Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Pro-Cys-NH2 ; Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Pro-Pen-NH2 ; Mpr (NG,NG' -ethylene-Har)-Gly-Asp-Trp-Pro-Cys-NH2 ; Mpr (NG,NG' -ethylene-Har-Gly-Asp-Trp-Pro-Pen-NH2 ; Mpr-Har-Sar-Asp-Trp-Pro-Cys-NH2 ; Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Pro-Pen-NH2 ; Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Pro-Cys-NH2, Mpr-Har-Sar-Asp-Trp-Pro-Pen-NH2 ; Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Pro-Pen-NH2 ; and Mpr-(Phenylimidyl-Lys)-Gly-Asp-Pen-NH2.